ANTHELMINTICS FOR ANIMAL USE

Anthelmintics/ Antihelminthics are drugs that expel parasitic worms

(helminths) from the body, by either stunning or killing them. - They may also be called
vermifuges (stunning/expelling) or vermicides (killing).

Ideal anthelmintic characteristics:

• wide margin of safety
• broad spectrum of activity
• selectively toxic to the parasite
• Good efficacy
• Easy to administer without complex dosing schedules
• Short residual effects in edible products
• Stable to chemical and environmental variables
• Economical
• considerable activity against immature (larval, ovoid) and mature stages of
helminthes
The selective toxicity to the parasite,is achieved either by inhibiting special
metabolic processes of worms, or by inherent pharmacokinetic properties of the
compound that cause the parasite to be exposed to higher concentrations of the
anthelmintic than the host cells. Helminths are divided into two major groups:-
Nematodes: cylindrical, nonsegmented worms commonly called roundworms;
Platyhelminths: flattened worms that are subdivided into two groups: Cestodes
(tapeworms) and Trematodes (flukes)

CLASSIFICATION OF ANTHELMINTICS

I. BASED ON ANTHELMINTIC SPECTRUM

• Drugs acting against roundworms (nematodes)- Antinematodals
• Drugs acting against apeworms (cestodes)- Anticestodals
• Drugs acting against flukes (trematodes)- Antitrematodals

II. BASED ON STRUCTURE

1. Benzimidazoles 11. Bisphenolic compounds

2. Probenzimidazoles 12. Sulphonamides
3. Imidazothiazoles 13.Natural organic compounds
4. Isoquinoline and benzazepin derivatives 14. Inorganic compounds
5. Organophosphates 15. Hexyloixynaphthamidines
6. Piperazines 16. Miscellaneous
7. Tetrahydropyrimidines
8. Salicylanilides and substituted phenols
9. Macrocyclic lactones (Avermectins and milbemycins)
10. Halogenated hydrocarbons
 ANTI NEMATODALS ANTI TREMATODALS ANTICESTODALS
Group Example Group Example Group Example
Benzimida Albendazole Halogenated Carbontetrachlori Prazinoisoqu Praziquantel
zoles hydrocarbon de inolones Epsiprantel
s Hexachloroethane
Hexachloroparax
ylene
Probenzi Febantel Salicylanilide Closantel, Salicylanilid Niclosamide
midazoles s Resorantel es Resorantel
Rafoxanide Dichlorophen
Ciloxanide
Oxyclozanide
Brotianide
Diamphenethide
Imidazothi Levamisole Nitrophenols Niclofolan Substituted Nitroscanate
azoles _ Disophenol phenols
Nitroxynil
Tetrahydr Pyrantel Bisphenolic Hexachlorophene Natural Alkaloids-
opyrimidi pamoate compounds Bithional organic Arecholine
nes sulfoxide compounds Nicotine
Bromsalans Cucurbitine;
Kamala,
Filicic
acid(Dryopte
res filiximas)
Piperazine Piperazine Benzimidazol Albendazole Inorganic Tin oxide
s DEC es Triclabendazole compounds Lead
Luxabendazole arsenate
Salicyla Closantel, Probenzimid Netobimin Hexyloixyna Scolaban
nilides azoles phthamidine Bunamidine
s

Substitute Nitroxynil Sulphonamid Clorsulon Benzimidazo Fenbendazol

d es les e
phenols Albendazole
Mebendazole
Oxfendazole
Macro Ivermectin, milbemycine Probenzimid Febantel
cyclic azoles
lactones
Organoph Haloxon, Dichlorovos
osphates
Miscellane Phenothiazine,Disophenol
ous Thiacetarsamide,
Dithiazine
 1. BENZIMIDAZOLES (BZ) AND PROBENZIMIDAZOLES (PBZ)

a. Thiazolil-benzimidazoles- Thiabendazole , Cambendazole

b. Benzimidazol-carbamates-(5-keto BZs, Sulphid-BZs)- Albendazole,

Flubendazole, Fenbendazole, Mebendazole, Oxfendazole (Oxfendazole
sulphoxide),Parbendazole, Oxibendazole, Ricobendazole (Albendazole
sulphoxide) , Thiophanate and Triclabendazole
c. Probenzimidazoles (pro-drugs)
Febantel→Fenbendazole→Oxfendazole (Oxfenbendazole)
Netobimin→Albendazole→Ricobendazole
Thiophanate→Lobendazole

Mechanism of action-
Primary effect:
• Inhibition of tubulin polymerization; by binding to the nematode tubulin, thus
inhibiting its polymerization or assembly into microtubules, leading to
degenerative alterations in the tegument and intestinal cells of the worm
Secondary effect:
• Inhibition of cellular transport and energy metabolism, are consequences of the
depolymerization of microtubules.
• The loss of the cytoplasmic microtubules leads to impaired uptake of glucose by
the larval and adult stages of the susceptible parasites, and depletes their glycogen
stores.
• Degenerative changes in the endoplasmic reticulum, the mitochondria of the
germinal layer, and the subsequent release of lysosomes result in decreased
production of adenosine triphosphate (ATP), which is the energy required for the
survival of the helminth.
• Due to diminished energy production, the parasite is immobilized and eventually
dies.
• The also have been shown to inhibit the enzyme fumarate reductase, which is
helminth-specific. This enzyme is an essential component of the fermentation by
which many parasites obtain their source of energy.
• They also induce sterility in worms by inhibiting the egg production and
uncoupling oxidative phosphorylation
Anthelmintic spectrum
• In ruminants, the benzimidazoles are most effective if deposited directly into the
rumen. Administration directly into the abomasum, via the esophageal groove, may
shorten the duration for drug absorption and increase the rate of excretion in the
feces, which may reduce efficacy.
Antinematodal effect
• Broad spectrum of activity against roundworms (nematodes)
• Larvicidal and ovicidal (Alb., Fenb., Feban., Oxf., Oxib.) effect
• Triclabendazole has no activity against roundworms
Anticestodal effect-Febantel, Fenbendazole, Netobimin, Albendazole, Mebendazole,
Oxfendazole, Flubendazole
 Antitrematodal effect (for flukes, Fasciola, Dicrocoelium, Paramphistomum spp.)
Netobimin, Albendazole, (only against adult stages of liver fluke) and Triclabendazole –
only liver fluke (Fasciola hepatica) effective against both immature and adult flukes

Pharmacokinetic features
• Only limited amounts of any of the benzimidazoles are absorbed from the GI
tract of the host (except e.g. Alb., Oxf., and Triclab.)
• The limited absorption is probably related to the poor water solubility of these
drugs. The little absorption that occurs is generally rapid, 2-7 hr after dosing with
flubendazole and 6-30 hr after dosing with albendazole, fenbendazole, and
oxfendazole, depending on the species.
• Many of the benzimidazoles and their metabolites re-enter the GI tract by
passive diffusion, but the biliary route is the most important pathway for
secretion and recycling of benzimidazoles to the GI tract..
• Absorption lasts for 6-30 h after dosing (Flub. 2-7 h).
• Rate of passage is slowed by the rumen or cecum (equine).or reduced feed intake
may increase the activity of BZs.
• The rumen acts as a drug reservoir from which plasma concentrations can be
sustained for long periods . ; it also slows the passage of unabsorbed drug
through the GI tract..
• BZs are sparingly soluble in water, they are given PO as a suspension, paste,
bolus or premix, (except Netobimin, which can be injected).
Metabolism
• of the benzimidazoles is variable and may alter their activity
• Eg. Albendazole is rapidly and reversibly oxidized to its sulphoxide.
Benzimidazole sulphoxides such as Oxfendazole and Albendazole sulphoxide
bind poorly to parasite β-tubulin and probably act as prodrugs for Fenbendazole
and Albendazole. - The sulphoxide may be irreversibly oxidized to its sulphone ,
which is significantly less active than the sulfoxide.
• The biliary route is the most important pathway for secretion and
(enterohepatic) recycling of BZs to the GI tract.
• Both, the unabsorbed amount of BZs and bile excreted parent drugs and their
metabolites are eliminated with faeces.

Side-Effects - PO relative safe, non-toxic agents

• Teratogenicity ( Rotational and flexural deformities and malformations of the limbs,
carpal joints) with most Albendazole, Parbendazole and Cambendazole
• Fenbendazole is the safest anthelmintic in pregnancy .
• No teratogenic effects were noticed with mebendazole, fenbendazoole, oxibendazole,
thiophanate
• Hepatotoxicity (thiabendazole, oxibendazole, mebendazole).
• Neurotoxicity
- Resistance may occur (GI-roundworms in ruminants), frequently multiply resistance
against BZs,
- - Thiabendazole is applied topically (as fungicide, or against cutaneous larva migrans),
has got anti-inflammatory action also.
- Withholding periods are between 8-14 days before slaughtering for meat, and 3-5 days
before milking , but are longer for bolus formulations

Albendazole
Albendazole, a broad-spectrum oral benzimidazole anthelmintic, is the drug of
choice for treatment of hydatid disease and cysticercosis. It is also a major drug for the
treatment of pinworm infection, ascariasis, trichuriasis, strongyloidiasis, and infections
with both hookworm species
Anthelmintic Actions:
• Albendazole and its metabolite albendazole sulfoxide are thought to act by
inhibiting microtubule synthesis in nematodes, thus irreversibly impairing
glucose uptake. As a result, intestinal parasites are immobilized or die slowly,
and their clearance from the gastrointestinal tract may not be complete until
several days after treatment.
• The drug also has larvicidal effects in hydatid disease, cysticercosis, ascariasis,
and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis, and
trichuriasis.
• The drug, is teratogenic and embryotoxic , is contraindicated in first trimester of
pregnancy
• Albendazole is administered on an empty stomach when used against
intraluminal parasites but with a fatty meal when used against tissue parasites.
• Mild and transient epigastric distress, diarrhea, headache, nausea, dizziness,
lassitude, and insomnia are the adverse effects

2. IMIDAZOTHIAZOLES
• Tetramisole, a racemic mixture (unsafe, recently not used)
• Levamisole, L-isomer form
• Butamisole HCl
Mechanism Of Action
• As agonists at excitatory nicotinic acetylcholine receptors of nematodes they are
ganglion-stimulant (cholinomimetic) - They stimulate ganglion-like structures in
somatic muscle cells of nematodes. This stimulation first results in sustained
muscle contractions, followed by a neuromuscular depolarizing blockade
resulting in spastic muscle paralysis due to prolonged activation of the nicotinic
acetylcholine (nACh) receptors
Anthelmintic spectrum
• Antinematodal with broad spectrum of activity- adulticidal, larvacidal (including .
Dirofilaria . immitis) , are not ovicidal
• Effective against ascarids, strongyles, whipworms, and hookworms
• No activity against flukes and tapeworms.
• Resistance to levamisole has been reported for nematodes of cattle (not serious).
• Nematodes resistant to Levamisole are cross resistant to Morantel (similar mode
of action).
• Levamisole is an anthelmintic with Immunomodulatory properties
(Immunostimulant)
 • It enhances the immune responses by modifying the activities of T-
lymohocyteds and phagocytes in immunologically depressed/ chronically ill
animals
• Immunimodulatory dose is 1/3 rd of anthelmintic dose given intermittently for
three days
Pharmacokinetic features

• The absorption and excretion of levamisole is rapid and not affected by the route
of administration or ruminal bypass because it is highly soluble. In cattle, peak
blood of levels <1 hr after SC administration
• Concentrations decline rapidly; 90% of the total dose is excreted in 24 h., largely
in the urine.
• Withholding periods for meat are short, and frequently there is no or only a
short, withholding period for milk.
Side-effects
• The safety index (SI) is narrow for Levamisole (SI = 4-6).
• Cats, Horses, and certain dog breeds (e.g. Kuvasz) are very sensitive.
• Toxic signs are: cholinergic-type signs of salivation, muscle tremors, ataxia,
urination, defecation, and collapse, asphyxia due to respiratory failure. /Antidote:
Atropine/
• Some transient inflammation at the site of SC injection.
• Contraindications: - Not indicated in lactating cattle
Dose: Ruminants, Swine, 5-7.5; Dogs 5; Poultry 10 mg/kg B.W. Normally is
administered PO or SC, and efficacy is generally considered equivalent with either route.
Immuniostimulant dose is 1/3rd(2.5mg/kg;SC) of anthelmintic dose . Topical
preparations (pour on) for cattle have been developed.

3. TETRAHYDROPYRIMIDINES
• Pyrantel Citrate, Tartrate salt: Cattle, Horses, Cats, Dogs, and Pigs
• Pyrantel Pamoate /Embonate/ salt: Horses and Dogs (Cats)
• Morantel citrate (The methyl ester analogue of pyrantel): Ruminants
• Oxantel
Mechanism of action
• It is a depolarizing neuromuscular blocking agent in nematodal parasite
• Irreversible Cholinomimetic activity, inducing contracture of the musculature
similar to the contraction induced by ACh, , leading to spastic paralysis.
• The action of Pyrantel can be antagonized by piperazine, which induces
nematodal muscle relaxation
Anthelmintic Spectrum
• Antinematodal effect (Relatively large spectrum against GI nematodes – the first
broad spectrum agents for against this parasites) . • Adult gut worms and larval stages
that dwell in the lumen or on the mucosal surface.
• Limited or no activity against migrating larvae, and Trichuris spp.
• Nematodes resistant to levamisole are cross-resistant to morantel due to the
similarities of their mechanisms of action.
• Safer in young puppies, pregnant and lactating animals
Pharmacokinetic features
• Pyrantel tartrate (or citrate) is well absorbed by pigs and dogs, poorly by
ruminants.
• Administration with food delays passage through digestive tract, prolonging the
contact time of the drug with the parasite, thereby increasing the efficacy.
• The pamoate salt is poorly soluble in water; this offers the advantage of reduced
absorption from the gut and allows the drug to reach and be effective against
parasites in the large intestine, which makes it useful in horses and dogs.
• Metabolism of pyrantel is rapid, and the metabolites are excreted rapidly in the
urine (40% of the dose in dogs); some unchanged drug is excreted in the faeces
(principally in ruminants).
• Blood levels usually peak 4-6 hr after PO administration.
• Morantel is absorbed rapidly from the upper small intestine of sheep and
metabolized rapidly in the liver; ~17% of the initial dose is excreted in the urine
as metabolites within 96 hr after dosing
• withholding periods for meat and milk are short /frequently no for milk/
Side-effects
• Cholinergic-types of signs. /Antidote: Atropine
• Morantel in Ruminants tends to be safer and more effective than pyrantel.
• Contraindications: severly debilitated animals, as the cholinergic
pharmacological actions are more pronounced in these animals

4. PIPERAZINES

• Piperazine (phosphate, adipate, citrate, sulfate, tartrate, HCl)

• Diethylcarbamazine citrate (DEC)

Mechanism of action
• Block neuromuscular transmission in the parasite by hyperpolarizing the nerve
membrane, which leads to flaccid paralysis, (reversible vermifuge effect, without
killing them)
• Also block succinate production by the worm. The parasites, paralyzed and
depleted of energy, are expelled by peristalsis.
• DEC disrupta the microtubule and inhibits the microtubule polymerisation in
immature Dirofilaria immitis , filaria, microfilaria
Anthelmintic Spectrum
• The spectrum of activity of Piperazine is largely against ascarid parasites in all
animal species. And Large doses against hookworms,pinworms and nodular
worms.
• Mature worms are more affected than larvae , and hence treatment may be
repeated at 2 weeks intervalk in dogs and cats and at 4 week interval in
ruminants
• Diethylcarbamazine is used for heartworm prevention in dogs; however, its use
is declining. In existing infections, the dogs must first be cleared of adult
 heartworms and microfilariae to avoid reaction, then are given DEC daily PO
throughout the mosquito season to prevent reinfection
• Diethylcarbamazine is a drug of choice in the treatment of filariasis,
Wuchereria bancrofti, , Brugia timori, . Onchocerca volvulus loaloaiasis, and
tropical eosinophilia.
• Diethylcarbamazine has shown in vivo and in vitro immunosuppressive actions,
the mechanism of which is imperfectly understood.
• Has also been used to treat prepatent Dictyocaulus viviparous infections
(lungworm infection) in cattle, (relatively ineffective against the adult worms).

Pharmacokinetic features
• Piperazine is rapidly absorbed from the GI tract,- Piperazine base can be detected
in the urine as early as 30 min. after administration.
• The excretion rate is maximal at 1-8 h, and excretion is practically complete
within 24 h.
• DEC is rapidly equilibrates with all tissues except fat. It is excreted, principally
in the urine, as unchanged drug and the N-oxide metabolite.
• Dosage may have to be reduced in patients with persistent urinary alkalosis or
renal impairment.
Side-effects
• The safety margin is wide (less in horses, puppies and kittens) with no
teratogenic effects
• Toxicity caused by to large doses includes vomiting, diarrhoea and ataxia.
• Adverse Reactions with DEC

a.Drug-Induced Reactions: Reactions to diethylcarbamazine itself are mild and

transient and start within 2-4 hours: headache, malaise, anorexia, and weakness are
frequent; nausea, vomiting, dizziness, and sleepiness occur less often. The drug
should be taken after meals.
b. Reactions Induced by Dying Parasites: Adverse effects also occur as a result of
the release of foreign proteins from dying microfilariae or adult worms in sensitized
patients. Eosinophilia and leukocytosis are usually intensified.

5. ORGANOPHOSPHATES

Originally pesticides
• Dichlorvos (Horses, Pigs, Dogs, and Cats)
• Cythioate (Dogs and Cats)
• Trichlorfon (Horses and Dogs)
• Naftalofos, Haloxon, Coumaphos, Crufomate (Ruminants)
Mechanism of action
• Irreversible acetyl cholinesterase(AChE) inhibition by phosphorylating their
esterification sites, this blocks cholinergic nerve transmission in the parasite,
which results in spastic paralysis.
Anthelmintic Spectrum
• Effective against GI-roundworms (and bots).
 • Limited efficacy against immature stages.
• Ineffective against migrating larvae tapeworms and flukes.
Pharmacokinetic features
• Good absorption after oral administration, readily penetration through
unbroken skin (high lipid solubility).
• Inactivation by the liver.
• Excretion mainly with urine; to a lesser extent with milk.
Side-Effects
• Narrow margin of safety.
• Signs of overdosing: restlessness, salivation, miosis, bradycardia, bronchial
constriction, diarrhoea, ataxia, tremors. - Strict attention to dosage is necessary.
• Topical formulations (sprays, collars, washes) can present significant hazards
to young infants of small animals after ingestion, inhalation, or transcutaneous
absorption. Basic liquids (soaps) inactivate them.
• Contamination of the environment through faecal excretion.
• Concurrent use of other cholinesterase-inhibiting drugs should be avoided.
• Antidotes: Atropine and 2-PAM-type enzyme-reactivators.

6. SALICYLANILIDES AND SUBSTITUTED PHENOLS

Salicylanilides
• Brotianide, Clioxanide, Closantel, Niclosamide, Oxyclozanide,
Rafoxanide

Substituted phenols
• Bithionol, , Dichlorophene Hexachlorophene, Niclofolan,
Menichlopholan, Nitroxynil, Disophenol and Diamphenethide (is an
aromatic amide) Nitroscanate (only in dogs)
Mechanism Of Action
• Uncoupling of oxidative phosphorylation processes
• These compounds act as protonophores, allowing hydrogen ions to leak through
the inner mitochondrial membrane.
Anthelmintic Spectrum
• They are used in sheep and cattle extensively against fasciolosis and
haemonchosis* (hematophagous nematodes, e.g. Haemonchus* and
Bunostomum).
• Lowered efficacy of a number of the salicylanilides and substituted phenols
against immature flukes may be due to the high protein binding of these drugs in
the blood.
• Diamfenetide (diamphenethide) is unique , having high activity against the
youngest immature stages, a diminution of activity as the flukes mature., thus
effective in acute fascioliasis
• They are generally ineffective against nematodes (due to a lack of drug uptake).
• Nitroscanate, Dichlorophen, and Nicliosamide are active against tapeworms
(Taenia spp., the first two drugs against Dipylidium, little or variable efficacy
against Echinococcus spp.)
 • Closantel is a endecticide, can be given both orally and parenterally (SC route)
• Oxyclozanide is effective against nasal schistosomiasis and adult liver flukes
• Rafoxanide is effective against nematodes, flukes, and tissue invading fly
maggots
Pharmacokinetic Features
• The fasciolicidal effects of salicylanilides (such as rafoxanide) in sheep depend
on persistence of the drug in plasma, which influences their transport throughout
the body and rate of elimination.
• Closantel, rafoxanide, and oxyclozanide have long terminal half-livesin sheep
(14.5, 16.6, and 6.4 days, respectively), which are related to the high plasma-
protein binding (>99%) of these 3 drugs.
• Secretion via the liver and bile is important for drugs active against adult
Fasciola spp., concentrations of fasciolocides and their metabolites are higher in
faeces than in urine.
• Residues in liver are detectable for weeks after administration., thus the need for
longer withholding periods.
• Oxyclozanide also is bound to plasma protein and then metabolized in the liver to
the anthelmintically active glucuronide and excreted in high concentration in the
bile duct, where it encounters the mature flukes.
• Diamfenetide is metabolized in the gut, and to a greater extent in the liver, to an
active metabolite that can enter hepatic cells and exert its antiparasitic effect
against very young stages of the fluke.
• Because rumen bacteria metabolize and destroy the activity of nitroxynil, it must
be injected.
• Nitroscanate is used in small animals against Toxocara , Toxascaris , Taenia ,
Dipylidium , Ancylostoma , Uncinaria , and Echinococcus spp . Vomiting
occasionally occurs after treatment
Side-Effects
• General uncouplers of oxidative phosphorylation, their side effects are lower
than those of many other anthelmintic agent.
• Mild anorexia and unformed faeces may be seen after treatment at recommended
dosages.
• High dosages may cause blindness, hyperthermia, convulsions, and death—
classic signs of uncoupled phosphorylation.
• Adverse effects are most commonly seen in animals that are severely stressed, in
poor condition nutritionally or metabolically, or that have severe parasitic
infections.

7. MACROCYCLIC LACTONES (AVERMECTINS AND MILBEMYCINS)

(Macrolide enedecticides)

Avermectins : Abamectin, Doramectin, Eprinomectin, Ivermectin,

and Selamectin
Milbemycins: Moxidectin, Nemadectin, Milbemycin oxime, MilbemycinD

Avermectins
 • These agents are potent ectoparasiticides as well , called as endectocides
• Structurally similar to macrolide group of antibacterials
• Semi-natural fermentation products of Steptomyces avermitilis and
cyanogriseus.

Milbemycins:
• Structurally slightly differ from avermectins, mainliy in the absenc of
disachharide group on C-13
• Moxidectin is derived semisynthetically, from the fermentation metabolite of
nemadectin, milbemycin being derived from Streptomyces hygroscopicus
• Highly lipophilic drugs, soluble in organic solvents and insoluble in water, the
residue concentrations found n fat tissues being ten times higher than those
reported for avermectins
Mechanism Of Action
• They act by GABA potentiation- potentiate the release of GABA (inhibitory
neurotransmitter) and activation of GABA gated chloride channels and
glutamate gated chloride channels (specific to parasites) at the excitatory motor
neurons (in nematodes) and myoneural junction (in arthropods)
• This causes the channel to open, allowing an influx of chloride ions.
• Cl- influx lowers cell membrane resistance and causes a slight hyperpolarisation
of the resting potential of post synaptic cells.
• As a result, neurotrsansmission of stimuli to the muscle is prevented , followed
by flaccid paralysis, subsequent death and expulsion.
• Mammalian GABA mediated transmission is limited to CNS and these agents
do not cross Blood brain barrier(except in collie breed dogs and Murray grey
cattle, some Australian shepherds due to genetic predisposition ) and hence have
wide margin of safety in mammals.
• Avermectins also interfere with reproduction of the partasites resulting in
reduced oviposition in ticks and abnormal egg laying in nematodes, sterility in
both male and female filarial nematodes

Anthelmintic Spectrum
• Active against both endo and ectoparasites- Endectocidal
• Active against all stages of nematodes(hypobiotic larvae) including GI
nematodes(Ascaris, Strongylus, Ostertagia, Haemonchus spp, etc), lung nematodes(
Dictyocalus filaria, Metastrongylus spp), eye worms( Thelazia spp.)
• Active against only the microfilarial stagees (immature heart worm) of many
filaroids, ineffective against adult filarial worms. It is not known whether this
stage differentiation is caused by the failure of the drug to reach the site of action
or the innate mechanistic insensitivity of the adult parasites
• Active against schistosomes and ectoparasites (arthropods).- tick, flea. mite,
horn flies, warbles, maggot fly bots
• No activity against cestodes and trematodes as they lack the GABA mediated
neurotransmission
• Resistance may occur (parallel with BZs and levamisole).
Doramectin:
 - Novel avermectin produced by mutational biosynthesis
- Broad range of activity against GI nematodes, lung worms, eyeworms,
sucking lice, grubs, ticks, mites and screw worms in cattle.
- Efficacy against the myiasis is unique among the macrocyclic lactones
- Can be administered SC and IM
- Other features being similar to ivermectin
Pharmacokinetic Features of avermectins and milbemycins
• Lipophilic compounds, good absorption, wide distribution.
• Regardless of their route of administration, macrocyclic lactones are distributed
throughout the body and concentrate in adipose tissue. While the magnitude of
lipophilicity differs among chemical types, the limited vascularization and slow
turnover rate of body fat and the slow rate of release or exchange of drug from
these lipid reserves prolongs the residence of drug in the peripheral plasma.
• Accumulation in fatty tissue, long lasting effect, residues.
• In ruminants, the macrocyclic lactones are, like benzimidazoles, most effective if
deposited directly into the rumen
• Concentrations of ivermectin are high in digesta sampled from the distal
intestine, indicating that biliary secretion is an important pathway for clearance
of macrocyclic lactones. This pathway also has been conclusively demonstrated
for clearance of benzimidazole compounds.
• The extended high concentration in bile is influenced by prolonged exchange of
drug from lipid reserves and the enterohepatic recycling of biliary compounds
through the portal and biliary pools.
• The macrocyclic lactones are mostly excreted in the feces, the remainder (<10%)
in the urine.
• Most macrocyclic lactones are also excreted in milk.
• No embryotoxic/teratogenic effects, safe for use in breeding and pregnant
animals
Adverse/ Side-Effects
• The safety index for the macrocyclic lactones is typically wide , but Abamectin
and Moxidectin are contraindicated in calves and foals <4 mo old.
• Mammalian safety appears to depend on p-glycoprotein activity in the blood-
brain barrier. , though horses are sensitive to some extent. Transcient pruritus,
cutanoeous oedema may occur in horses following oral or IM treatment,
attributed to death of the microfilariae.
• Cattle breeds (Murray Grey) and purebred and crossbred Collies are most
sensitive for ivermectin toxicity
• Moxidectin injectable can be used in ivermectin sensitive collies
Toxicity signs: Nervous signs (idiosyncratic reactions) including ataxia,
depression, muscle weakness, blindness, coma, and death were observed, especially
in Collies.
• Physostigmine, with supportive fluid therapy helps in countering the milder
form of toxicity signs
• Milbemycin oxime has greater margin of safety in ivermectin sensitive collies
and in microfilaremic dogs
Problem of environmental burden/hazard: The avermectins are largely excreted in
feces and they bind to the soil and suppress the larvae(breeding) of some the soil /
dung degrading Diptera insects (dung beetle- Onthophagus gazella ) even up to 4
weeks following the treatment.. Thus the residue concentration of avermectins persist
for a longer time( several weeks) in the pasture soil grazed by the treated animals,
before getting slowly degraded.

Application
Ivermectin and doramectin-1% injectable, 10 mg tablets, 1% pour on
• SC- injection- Ruminants 0.2 (200µg/kg, strict SC), Swine 0.3 mg/kg B.W.
• PO- Swine premix, Horses paste, Dogs tablets
• Dermal- (spot on, pour on) 0.6-0.8 mg/kg B.W.

Milbemycins: Moxidectin – 1% injectable, , 0.1% . oral drenchs , 0.5% pour on

solution, 7.5, 15, 30 µg tablets ( oral and Inj Dose-200µg/kg,
Pour on - 500µg/kg)
Milbemycin oxime-5,7.5mg,11.5,23mgtablets,(dose- 0.5- 0.99mg/kg-
dog; 2mg/kg-cats) ; recently has been combined with Lufenuron in a
tablet formulation for the simultaneous prevention and control of flea
infestations and nematodes

Treatment of Heartworm Disease

Heartworm disease is caused by the filarial nematode Dirofilaria immitis

• Three stages of management of heartworm disease
– Preventing third-stage larvae from reaching maturity (preventative)
– Adulticide therapy
– Eradication of circulating microfilariae after infection
• Preventing third-stage larvae from reaching maturity (preventative)
– Daily oral preventative
• Diethylcarbamazine (DEC)
– Given during mosquito season and two months after
– Patient must be heartworm negative
– Once-monthly oral preventatives
• Ivermectin
• Milbemycin
– Once-monthly topical preventative
• Selamectin
– Six-month injectable preventative
• Moxidectin
• Adulticide therapy
– Melarsomine
• Given in the epaxial muscles
• Less toxic than former drug (thiacetarsamide)
• Side effects include nephrotoxicity and hepatotoxicity
• Eradication of circulating microfilariae after infection
– Ivermectin (given at higher dose as a microfilaricide)
– Milbemycin
 – Levamisole (infrequently used)
Heart worm adulticides(Anti nematodals) : are organic arsenical compounds

1. Thiacetarsamide sodium

• Administered IV, (2.2mg/kg) ,irritant to tissues; avoiding

extravasation
• Hepatotoxic and nephrotoxic
• Arsenic toxicity menifestated as persistent vomition, icterus,
orange coloured urine ; can be treated with Dimercaprol(BAL;
8.8mg/kg/day in 4 divided doses)
2. Melarsomine

• Dihyrochloride salt , reconstituted with 0.9% normal saline

(2.5mg/kg;IM)
• Localized oedema, distress, restlessness, salivation,
tachycardia- toxicity signs are similarly treated as above.

8 MISCELLANEOUS/OTHERS ANTHELMINTICS (ANTI NEMATODALS)

PHENOTHIAZINE
• Sterilizes the worms by inhibiting egg production and destroying the hatched
larvae
• Not used nowadays(limited, only in swines), because of its metabolite-
phenothiazine sulfoxide, causing photosensitization resulting in corneal ulcers

DISOPHENOL
• Active aginst hook worms( Ancylostoma caninum) of canines
• Acts by uncoupling the oxidative phosphorylation
Highly irritant on SC injection, not used nowadays

9 . ISOQUINOLIN AND BENZAZEPIN DERIVATIVES ( Prazino isoquinolones )

Dealt under Anticestodal agents
ANTI TREMATODAL AGENTS

1. HALOGENATED HYDROCARBONS

Carbontetrachloride

• Inhibits cholesterol syntheisis in host liver

• Accumulation of methyl sterols, (toxic to host also), taken up by flukes and
subsequently get killed
• Potent hepatotoxic, use declined now
 2. BISPHENOLIC COMPOUNDS

Bithionol
• It l is the drug of choice for the treatment of sheep fascioliasis (sheep liver fluke)
• Bithionol is also an alternative drug in the treatment of pulmonary
paragonimiasis. (lung fluke)
• The mode of action of bithionol against Paragonimus westermani has not been
established.
• Hexachlorophene is the other agent

3. SALICYLANILIDES

Closantel, Resorantel Rafoxanide Ciloxanide Oxyclozanide Brotaianide

Diamphenethide are the commonly used ones
• Highly effective against adult rumen flukes (Amphistomes and Paramphistomes)
and tissue flukes
• The reason for mature flukes benig more vulnerable, than immature flukes to most
of the fasciolicides:
Immature flukes in the liver parenchyma ingest mainly
liver cells, which contain little anthelmintic; plasma-protein binding
limits entry of the drug into the tissue cells. As the flukes grow and
migrate through the liver, they cause extensive hemorrhaging and
come into contact with anthelmintic bound to plasma protein.
When they reach the bile ducts, they are in the main excretory
hannels for the active metabolites of the fasciolicides and are
exposed to toxic concentrations.
• Diamphenethide is metabolized in the gut, and to a greater extent in the liver,
to an active metabolite that can enter hepatic cells and exert its antiparasitic
effect against very young stages of the fluke. , the mechanism of action being
similar to praziquantel causing vacoulation and death

4. SUBSTITUTED (NITRO) PHENOLS

• Niclofolan , Nitroxynil, Disophenol

5 BENZIMIDAZOLES

Netobimin, Albendazole, (only against adult stages of liver fluke,

Fasciola, Dicrocoelium, Paramphistomum spp.)
Triclabendazole – active only against liver fluke (Fasciola hepatica) and
effective against both immature and adult flukes

6 CLORSULON
 • Aminobenzene disulphonamide derivative
• Clorsulon is a sulfonamide given PO as a suspension for infections with
(mainly) adult liver flukes in sheep and cattle and as a SC injection for cattle,
in combination with ivermectin
• In plasma, clorsulon is bound to protein and, when ingested by liver flukes,
inhibits enzymes of the glycolytic pathway in liver flukes. (cellular energy
production is disrupted).
• Although its safety margin is wide, clorsulon is not licensed for use in
lactating dairy cows producing milk for human consumption

7. EMETINE HYDROCHLORIDE
• Emetine and dehydroemetine (less toxic than emetine) are alternative drugs for
the treatment of Fasciola hepatica infection.
• Both drugs are sometimes effective but are more toxic than triclabendazole or
bithionol (the drugs of choice).

ANTI CESTODAL AGENTS

1. ISOQUINOLIN AND BENZAZEPIN DERIVATIVES ( Prazino isoquinolones )

• Praziquantel and Epsiprantel (closely related analogs)

• Most widely used and safest Anticestodal- praziquantel HCl

Mechanism of action
• Induction of spastic paralysis in the parasite., the drug increases cell membrane
permeability to calcium, resulting in vacuolization, marked contraction,
paralysis, dislodgement, and death
 • Primarily action is on neuromuscular coordination, by interfering with the
regulation of intracellular Ca2+ concentrations, impairing both motility and
function of the suckers of the cestode.
• In schistosome infections of experimental animals, praziquantel is effective
against adult worms and immature stages; adult worms are rapidly immobilized
and then passively shift to the liver.
• In addition, when a single high dose of praziquantel is given concurrently with
an infecting dose of cercariae, all immature forms are killed; thus, praziquantel
has a prophylactic effect.

Anthelmintic spectrum
• Anticestodal effect (against tapeworms). -- High efficacy against mature and
larval cestode parasites including Echinococcus spp (Hydatid disease). and
against certain trematodes (blood flukes).
• Praziquantel is effective in the treatment of schistosome infections of all
species and most other trematode and cestode infections, including cysticercosis
• Not effective against nematodes and liver flukes ( Fasciola hepatica)
• Epsiprantel is effective against Taenia and Dipylidium, but not Echinococcus
Pharmacokinetic features
• Rapid and almost complete absorption from the GI
• Distribution to all organs (reenter gut lumen via bile and mucosa)
• Rapid hydroxylation into inactive forms in the liver and secretion in bile.

Side-Effects
• Wide safety margin, practically non-toxic.

2. NICLOSAMIDE
• salicylanilide derivative.
• It is minimally absorbed from the gastrointestinal tract: neither the drug nor its
metabolites have been recovered from the blood or urine.
• Following oral administration in animals and humans, no hematologic, renal, or
hepatic abnormalities have been noted.
• Scoleces and segments of cestodes, but not ova are rapidly killed on contact
with niclosamide
• The drug interferes a) with energy metabolism and reduce glucose uptake b)
depletes glycogen stores in worms c) interferes with mitochondrial action of
cestodes and uncouples/ inhibition of oxidative phosphorylation or to its
ATPase- over stimulating property leading to energy deficiency and the death..
With the death of the parasite, digestion of scoleces and segments begins.
 • Safer in pregnant and debilitating animals
• Indicated in dog, cat tapeworms and sheep Moneziasis
• Adverse Reactions : infrequent, mild, and transitory. Nausea, vomiting,
diarrhea, and abdominal discomfort

3. DICHLOROPHEN
MOA and Indications similar to niclosamide

4. RESORANTEL
Inhibits glucose degradation pathway and terminal stages of glucose pathway

5. NITAZOXANIDE

Nitazoxanide, a pyruvate ferredoxin oxidoreductase inhibitor, acts against a broad

spectrum of protozoa and helminths that occur in the intestinal tract
It is currently used for the treatment of protozoal infections.
The site of action of this compound has not been established in nematodes although
anaerobic electron transport enzymes may be a potential target
The efficacy of this compound is relatively low compared to other anticestodal agents.

6. BUNAMIDINE (HCl, hydroxynapthoate salts)

• Naphtamidine compound.
• Used in small animals, leads to digestion of tapeworms in the gut of the host, due
to an inhibition of glucose uptake of worms.
• Most effective if given after fasting.
• It is absorbed and metabolized in the liver., Hepatotoxic_ not given routinely
• Vomiting and mild diarrhoea may be seen, and exercise or excitement should be
avoided in dogs soon after administration.

8. NATURAL ORGANIC COMPOUNDS

• Plant origin
• Possibility of recovery of worm
• Given in combination with purgative
• Worms are paralysed and eliminated
• Low efficacy of the compounds

Arecholine
• Areca catechu derived alkaloid
Nicotine
• Nicotiana tabaccum
Cucurbitine
• Pumpkin (Cucurbita pepo) seeds
 Kamala
• Mallotus phillippinensis glands of fruits – for cat tapeworm
Filicic acid
• Dryopteres filiximas dried rhizome

9. INORGANIC COMPOUNDS

Tin oxide and Lead arsenate are highly toxic with low margin of safety, have been
discontinued

10. BENZIMIDAZOLES - Fenbendazole ,Albendazole, Mebendazole and

oxfendazole

NEWER ANTHELMINTICS

Due to the development of drug resistance, there is a continual need for newer
anthelmintics with novel and different mode of action

1. EMODEPSIDE (CYCLODEPSIPEPTIDES)

Newer anticestodal and antinematodal, novel mode of action

The cyclo octa depsipeptide molecule, emodepside, is a semi-synthetic derivative of a
fermentation product obtained from the fungus, Mycelia sterilia, (Camelia
japonica) .
It is effective against isolates of parasites that are resistant to benzimidazole, levamisole
and ivermectin
The molecule has pore-forming properties in planar lipids, which does not appear to be
important in conferring its anthelmintic potency as an optical isomer of
emodepside, with similar pore forming properties, does not have anthelmintic
action.
It may act through stereospecific binding to a receptor, latrophilin which has homology
to mammalian latrophilins, a class of G protein-coupled receptors which bind the
neurotoxin, latrotoxin. Latrotoxin paralyses mammals by triggering
neurotransmitter release. Emodepside may cause paralysis of nematodes by
stimulating excessive neurotransmitter release at neuromuscular sites.
( NOTE: The pharmacology and details of these newer anticestodal agents :
DESASPIDIN , FLUXANE and MARNATOL ; which I could not find in many of
the articles or books so far. Any information with regard to these agents may kindly be
uploaded in scribd or may be sent to my mail ID: sunivet29@rediffmail.com )